U.S. patent number 11,260,943 [Application Number 16/719,371] was granted by the patent office on 2022-03-01 for implantable micro-sensor to quantify dissolved inert gas.
This patent grant is currently assigned to CALIFORNIA INSTITUTE OF TECHNOLOGY. The grantee listed for this patent is CALIFORNIA INSTITUTE OF TECHNOLOGY. Invention is credited to Emil P. Kartalov, Axel Scherer.
United States Patent |
11,260,943 |
Kartalov , et al. |
March 1, 2022 |
Implantable micro-sensor to quantify dissolved inert gas
Abstract
Methods and devices including implantable micro-sensors used to
detect tissue-dissolved inert gas and to detect microbubble
formation to avoid Caisson disease are described. The disclosed
methods and devices are based on measuring the refractive index
changes in hydrophobic liquids after absorbing an inert gas such as
nitrogen. The changes in the refractive index are based on
implementing one of an interferometry, optical microcavity
resonance shift, a photonic crystal resonance, a beam deflection, a
resonance tuning or detuning, an amplitude change, or an intensity
change method.
Inventors: |
Kartalov; Emil P. (Monterey,
CA), Scherer; Axel (Pasadena, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
CALIFORNIA INSTITUTE OF TECHNOLOGY |
Pasadena |
CA |
US |
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Assignee: |
CALIFORNIA INSTITUTE OF
TECHNOLOGY (Pasadena, CA)
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Family
ID: |
1000006145732 |
Appl.
No.: |
16/719,371 |
Filed: |
December 18, 2019 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20200216155 A1 |
Jul 9, 2020 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62790151 |
Jan 9, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N
27/221 (20130101); B63C 11/02 (20130101); G01N
21/41 (20130101) |
Current International
Class: |
B63C
11/02 (20060101); G01N 27/22 (20060101); G01N
21/41 (20060101) |
Field of
Search: |
;405/186 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2017/027643 |
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Feb 2017 |
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WO |
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2020/146106 |
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Jul 2020 |
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WO |
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Other References
International Preliminary Report on Patentability for International
Application No. PCT/US2019/067170 filed on Dec. 18, 2019, on
behalfof California Institute of Technology, dated Jul. 22, 2021.
10 Pages. cited by applicant .
International Search Report and Written Opinion for International
Application No. PCT/US2019/067170 filed on Dec. 18, 2019 on behalf
of California Institute of Technology, dated Apr. 14, 2020. 15
Pages. cited by applicant.
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Primary Examiner: Mayo-Pinnock; Tara
Attorney, Agent or Firm: Steinfl + Bruno, LLP
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims priority to U.S. Provisional
Application 62/790,151 filed on Jan. 9, 2019, the contents of which
are incorporated herein by reference in their entirety.
Claims
What is claimed is:
1. A sensor comprising: a micro-chamber capsule filled with a
hydrophobic liquid; and a measurement unit connected with the
micro-chamber capsule; wherein the measurement unit is configured
to: detect and quantify a concentration of an inert gas by
measuring a physical change of the hydrophobic liquid due to a
dissolving of the inert gas in the hydrophobic liquid, generate
measured results; the physical change is a change in a refractive
index of the hydrophobic liquid, and the measurement unit measures
the change in the refractive by implementing one of an
interferometry, optical microcavity resonance shift, a photonic
crystal resonance, a beam deflection, a resonance tuning or
detuning, an amplitude change, or an intensity change method.
2. The sensor of claim 1, wherein the hydrophobic liquid comprises
one of lipid, gel, or oil.
3. The sensor of claim 1, wherein the inert gas comprises one of
nitrogen, helium, neon, krypton, argon, or a mixture thereof.
4. The sensor of claim 3, wherein dimensions of the micro-chamber
capsule are on a scale of microns, tens of microns, or hundreds of
microns.
5. The sensor of claim 4, wherein the sensor is implantable in
animal or human subjects.
6. An electronic system comprising a sensor and a wearable monitor,
the sensor comprising: a micro-chamber capsule filled with a
hydrophobic liquid; and a measurement unit connected with the
micro-chamber capsule, wherein: the measurement unit is configured
to detect and quantify a concentration of an inert gas by measuring
a physical change of the hydrophobic liquid due to a dissolving of
the inert gas in the hydrophobic liquid, and generate measured
results; the measurement unit is configured to communicate with and
transmit the measured results to the wearable monitor; the sensor
in inductively powered by the wearable monitor; the inert gas
comprises one of nitrogen, helium, neon, krypton, argon, or a
mixture thereof; dimensions of the micro-chamber capsule are on a
scale of microns, tens of microns, or hundreds of microns, and the
sensor is implantable in animal or human subjects.
7. A method of detecting and quantifying a concentration of an
inert gas dissolved in a hydrophobic liquid, comprising: measuring
a physical change of the hydrophobic liquid due to the dissolving
of the inert gas in the hydrophobic liquid; and providing measured
results including the concentration of the inert gas, wherein the
physical change is a change in a refractive index of the
hydrophobic liquid, and the measuring comprises implementing one of
an interferometry, optical microcavity resonance shift, a photonic
crystal resonance, a beam deflection, a resonance tuning or
detuning, an amplitude change, or an intensity change method.
8. The method of claim 7, wherein the hydrophobic liquid comprises
one of lipid, gel, or oil and wherein the inert gas comprises one
of nitrogen, helium, neon, krypton, argon, or a mixture
thereof.
9. A method of detecting and quantifying a concentration of an
inert gas dissolved in a hydrophobic liquid, comprising: applying
the inert gas with a known ambient pressure and a known
concentration to the hydrophobic liquid, the hydrophobic liquid
comprising one or lipid, gel or oil, and the inert gas comprising
one of nitrogen, helium, neon, krypton, argon, or a mixture
thereof; waiting for equilibration; taking titrated measurements of
a physical change of the hydrophobic liquid due to the dissolving
of the inert gas in the hydrophobic liquid, thereby calibrating the
measured results in real time; and providing measured results
including the concentration of the inert gas.
10. The method of claim 9, further comprising wirelessly
transmitting the measured results to a wearable monitor; and
displaying the measured results by the wearable monitor.
11. The method of claim 10, further comprising: filling a
micro-chamber placed in a micro-chip with the inert gas; implement
the measuring on the micro-chip; implanting the micro-chip in a
body of a diver wearing the variable monitor; and combining the
measured results with a pre-programmed diving chart saved in the
wearable monitor to generate a diving plan for the diver.
12. A method of detecting and quantifying microbubble formation of
an inert gas dissolved in a hydrophobic liquid, comprising:
measuring a physical change of the hydrophobic liquid due to the
dissolving of the inert gas in the hydrophobic liquid; and
providing measured results including the concentration of the inert
gas, wherein the physical change is a change in a refractive index
of the hydrophobic liquid, and the measuring comprises implementing
one of an interferometry, optical microcavity resonance shift, a
photonic crystal resonance, a beam deflection, a resonance tuning
or detuning, an amplitude change, or an intensity change
method.
13. The method of claim 12, wherein the hydrophobic liquid
comprises one of lipid, gel, or oil and wherein the inert gas
comprises one of nitrogen, helium, neon, krypton, argon, or a
mixture thereof.
14. A method of detecting and quantifying microbubble formation of
an inert gas dissolved in a hydrophobic liquid, comprising:
measuring a physical change of the hydrophobic liquid due to the
dissolving of the inert gas in the hydrophobic liquid, the
hydrophobic liquid comprising one of lipid, gel, or oil and the
inert gas comprising one of nitrogen, helium, neon, krypton, argon,
or a mixture thereof; and providing measured results including the
concentration of the inert gas, wherein the physical change is a
change in turbidity and the measuring comprises applying light to
the hydrophobic liquid and quantifying one of: a) an intensity of
the light; b) an increased scattering of the light; c) a switching
from specular to diffusion of the light; d) a shift in a reflection
of the light; and e) a shift in refraction of the light, and
wherein the hydrophobic liquid comprises one of lipid, gel, or oil
and wherein the inert gas comprises one of nitrogen, helium, neon,
krypton, argon, or a mixture thereof.
15. A method of detecting and quantifying microbubble formation of
an inert gas dissolved in a hydrophobic liquid, comprising:
measuring a physical change of the hydrophobic liquid due to the
dissolving of the inert gas in the hydrophobic liquid, the
hydrophobic liquid comprising one of lipid, gel, or oil and the
inert gas comprising one of nitrogen, helium, neon, krypton, argon,
or a mixture thereof; providing measured results including the
concentration of the inert gas, and wirelessly transmitting the
measured results to a wearable monitor; and displaying the measured
results by the wearable monitor.
16. The method of claim 15, further comprising: implementing the
micro-chamber and the measuring on a micro-chip; filling the
micro-chamber with the inert gas; implanting or injecting the
micro-chip in a body of a diver wearing the wearable monitor; and
combining the measured results with a pre-programmed diving chart
saved in the wearable monitor to generate a diving plan for the
diver.
17. The method of claim 16, wherein the injecting is performed into
a subdermal space underneath the wearable monitor.
Description
FIELD
The presented disclosure is related to micro-sensors, in particular
implantable micro-sensors to quantify dissolved inert gas, and more
particularly to implantable micro-sensors used to detect
tissue-dissolved nitrogen and to detect microbubble formation to
avoid e.g. Caisson disease.
BACKGROUND
Throughout this document the term "tissue-dissolved" will refer to
"dissolved in tissue", with particular reference to the biological
tissue of the diver.
Caisson disease (known also as "the bends") is a potentially lethal
health risk for divers breathing a nitrogen gas mixture. As
pressure increases with depth, nitrogen dissolves in the tissues of
the diver. When the diver ascends, the positive pressure difference
stimulates bubble formation in the tissues and blood vessels,
potentially causing serious tissue damage, embolism, and possibly
death. Generally, the reason for breathing mixtures to contain an
inert gas is because pure oxygen is toxic as it is highly reactive
and will burn tissues. In the atmosphere, oxygen is diluted by
nitrogen, therefore human lungs can withstand it. A diver generally
requires a similar setup. For simple shallow dives, divers usually
use compressed air, which is inexpensive and already comes at the
necessary ratio between oxygen and an inert gas. For deeper dives,
divers use more complex mixtures of other inert gasses, e.g.
helium. However, any inert gas that does not have its own
biological system of efficient transport through the blood (as
oxygen and carbon dioxide have through hemoglobin binding) will
produce the same or similar decompression problem.
To help avoid these risks, divers time the ascent in accordance
with diving charts, to allow for the excess nitrogen to be exhaled
safely. However, the charts are only approximate, while biological
variability and the relative randomness of bubble formation produce
significant uncertainty. Moreover, slow ascent might be
impracticable in cold environments, hostile waters, or clandestine
missions. Slow ascent might also be undesirable in emergencies.
SUMMARY
The teachings of the present disclosure address the problems
described in the previous section and provide methods to measure
the concentration of nitrogen dissolved in tissues and monitor
microbubble formation. The described methods and devices may also
use the output of that measurement in combination with diving
charts and depth information to form a "diving solution"
recommendation to the diver in real time using a handheld/wearable
monitor.
The property of nitrogen and other inert gases to preferentially
absorb into hydrophobic environments is known to the person skilled
in the art. This property is known as part of the current
understanding of the mechanism of nitrogen narcosis, where nitrogen
dissolves in the cell membranes, which are made of a double layer
of lipids. The disclosed devices and methods use such property to
build implantable sensors.
Further aspects of the disclosure are provided in the description,
drawings and claims of the present application.
According to a first aspect of the present disclosure, a sensor is
provided, comprising: a micro-chamber capsule filled with a
hydrophobic liquid; and a measurement unit connected with the
micro-chamber capsule; wherein the measurement unit is configured
to: detect and quantify a concentration of an inert gas by
measuring a physical change of the hydrophobic liquid due to a
dissolving of the inert gas in the hydrophobic liquid; and generate
measured results.
According to a second aspect of the present disclosure, a method of
detecting and quantifying a concentration of an inert gas dissolved
in a hydrophobic liquid is disclosed, providing: measuring a
physical change of the hydrophobic liquid due to the dissolving of
the inert gas in the hydrophobic liquid; and providing measured
results including the concentration of the inert gas.
According to a third aspect of the present disclosure, a method of
detecting and quantifying microbubble formation of an inert gas
dissolved in a hydrophobic liquid, comprising: measuring a physical
change of the hydrophobic liquid due to the dissolving of the inert
gas in the hydrophobic liquid; and providing measured results
including the concentration of the inert gas.
DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an electronic system according an exemplary embodiment
of the present disclosure.
FIG. 2A shows a flowchart illustrating methods according to the
teachings of the present disclosure
FIG. 2B shows examples of physical changes in a hydrophobic liquid
after absorbing an inert gas such as nitrogen.
DETAILED DESCRIPTION
FIG. 1 shows an electronic system (100) comprising a sensor (110)
and a wearable monitor (120) in accordance with an embodiment of
the present disclosure. The implantable sensor (110) comprises a
micro-chamber capsule (111). Throughout this document the term
"capsule" will mean "enclosed chamber". In accordance with a
further embodiment of the present disclosure, the measured data may
be transmitted wirelessly from the measurement unit (112) to the
wearable monitor (120), as shown by the arrow (130). The wearable
monitor (120) may provide power to the implantable sensor (110) as
shown by the arrow (140). Dimensions of the micro-chamber capsule
may be on the scale of microns, tens of microns or hundreds of
microns. As also shown in FIG. 1, the sensor (110) may optionally
be implemented on a microchip (113)
In accordance with the teachings of the present disclosure, the
micro-chamber (111) may be filled by a hydrophobic liquid such as
lipid, gel, or oil. Physical properties of the hydrophobic liquid
may change due to absorption of an inert gas such as nitrogen,
helium, neon, krypton, argon, or a mixture thereof. The change of
such physical properties is then detected and measured by
measurement unit (112) by using for example electronic or
interferometric techniques. Moreover, the change in physical
properties of the liquid due to the absorption of the gas (e.g.
nitrogen) can then be calibrated within the measurement unit and
with known nitrogen concentration. In what follows, the disclosed
concept will be described more in detail and through some exemplary
embodiments.
As an example, absorption of nitrogen would change the refractive
index of the working liquid. In an exemplary embodiment,
interferometric techniques may be used to detect and measure the
changes in the refractive index. These techniques have been shown
to be miniaturizable, particularly with the use of photonic
crystals, Bloch arrays, and the use of optical micro-cavities etc.
In accordance with further embodiments of the present disclosure,
to help miniaturization, the actual detection may be set up to be
looking for a tuning or detuning shift of preset magnitude. Other
embodiments in accordance with the present disclosure may be
envisaged where an array of sensors such as the implantable sensor
(110) of FIG. 1 are implemented in a microchip where an overall
calibration may be performed by varying the shift across the array.
The change in the refractive index may be measured using various
techniques such as interferometry, Optical microcavity resonance
shift, photonic crystal resonance, beam deflection, resonance
tuning or detuning, amplitude change, or intensity change.
In an alternative embodiment in accordance with the present
disclosure, the measurement unit (112) comprises micro-fabricated
and micro-patterned electrodes to measure the electrical
capacitance or conductivity in the micro-chamber capsule (111) to
detect the absorbed gas (e.g. nitrogen). Using micro-fabricated and
micro-patterned electrodes improves the sensitivity of
measurements. Absorption of nitrogen would provide additional
diatomic molecules to the liquid (acting as a dielectric) within
the micro-chamber capsule (111), additional diatomic molecules
being subject to dielectric polarization when an electric field is
applied. The change in dielectric constant can then be measured by
the measurement unit (112). This effect can be amplified by adding
metallic particles to the micro-chamber material. As the
hydrophobic material is compressed or expands with the introduction
of inert gas, the metallic particles change the conductivity of the
metal/polymer composite, and change the measured capacitance or
conductivity that is measured.
According to embodiments of the present disclosure, the measurement
unit (112) may be made based on optical measurements of turbidity
to detect the onset of microbubble formation. In the absence of
bubbles, the liquid (e.g. lipid or oil) inside the micro-capsule
(111) is optically clear. When microbubbles start forming, they
would act as optical scatterers increasing the apparent turbidity
of the liquid. Alternatively, the optical measurement may be based
on a reflection, which will turn from specular to diffusive when
the microbubbles start forming. Both techniques may be implemented
based on an intensity measurement, which is known to be easily
miniaturizable. Other embodiments in accordance with the present
disclosure may also be made wherein the microbubble formation is
detected by measuring the electrical conductivity and/or
capacitance of the liquid inside the micro-chamber capsule (111).
In such a case, the measurement unit (112) comprises, preferably,
micro-fabricated and micro-patterned electrodes. The formation of
the bubbles will displace the dielectric liquid away from the
electrodes, thereby lowering capacitance and/or conductivity of the
system, depending on what liquid is used.
FIG. 2A shows a general flowchart (200) illustrating the disclosed
methods where first a physical change due to absorption of a gas in
a liquid is detected and measured, and the measured results are
then transmitted to a wearable device. Examples of such physical
changes are summarized in FIG. 2B. Various exemplary electrical and
optical techniques that can be used to measure such changes were
described in the previous paragraphs.
Referring back to FIG. 1, the electronic system (100) can be used
to improve safety and efficiency of diving operations. During a
diving operation, the wearable monitor (120) may be worn by the
diver, and the implantable sensor (110) is implanted or injected in
the diver's body. As an example, a small incision can be made in
the skin and the microchip is inserted in the incision under the
skin. The incision is sufficiently small such that the skin can
just be glued closed (no stitches required). Alternatively, the
device can be miniaturized to fit through an injection needle, and
inserted into the subdermal space underneath the reader. The
recovery is very quick (full heal within a week) due to the small
size of the incision. The wearable monitor (120) communicates
wirelessly with the implantable sensor (110) to provide diver with
the measured results. According to various embodiments of the
present disclosure: Power is supplied to the implantable sensor
(110) by the wearable monitor (120) through electromagnetic
induction. The implantable sensor (110) is fabricated on a
micro-chip. The wearable monitor (120) may use the received
measured results from the implantable sensor (110) to provide
visual or sonic feedback to the diver or the user wearing the
wearable monitor (120). The wearable monitor (120) may be a
handheld device. The wearable monitor can be part of a
health-monitoring system that includes other sensors and provides
integrated output to external monitoring systems. The wearable
monitor may be connected to that system wirelessly or by wire as
part of a wearable biomedical suit. Measuring the nitrogen
concentration e.g. by the measurement unit seeing a shift in the
absorption maximum may be independent of using turbidity to measure
microbubble formation. The nitrogen concentration can be converted
into partial pressure and compared to the ambient pressure to
produce a risk assessment of bubble formation, with its own three
zones defined (green, yellow, red). Low risk may be represented as
"green status". Higher risk may be represented as "yellow" or "red"
to the diver. The microbubble turbidity measurement can
independently indicate if bubbles are formed or not. That is a
"yes/no" measurement in general, but some calibration may be
performed to graduate it into zones if desired, e.g. based on the
quantification of the measured turbidity and some calibration to
the severity of microbubble formation. Both measurement (inert gas
concentration) and bubble turbidity may be implemented on the same
chip with both outputs transmitted to the wearable device to
display. The measured data may be combined with preprogrammed
diving charts and measured depth to calculate the best plan for
ascent and change it dynamically as new data is received in real
time. Further biometrics may also be tied in. The measured data may
be calibrated offline without involvement of the diver and then
used in real time. This is performed by applying a known ambient
pressure and concentration of the inert gas (e.g. nitrogen), then
waiting for equilibration followed by performing titrated
measurements to be used to calibrate the measured data.
* * * * *